Principles for Maximizing the Safety of Dermatologic Drug Therapy

Questions

Q2.1 What four words characterize the overall approach to maximizing drug safety, and what general concepts are represented by these words? (Pg. 12)
Q2.2 How are the ‘standards of care’ for drug therapy monitoring determined? (Pg. 13)
Q2.3 What are several of the typical characteristics of the most worrisome adverse effects to systemic drug therapy (Pg. 13)
Q2.4 In general, what are the most important issues to discuss with a patient before initiating systemic drug therapy which has a significant element of risk? (Pg. 14)
Q2.5 What are three broad categories for mechanisms for drug interactions which can assist clinicians in anticipating important potential drug interactions? (Pg. 15)
Q2.6 What are three to four examples of major drug risks ‘discovered’ many years after the drug’s release? (Pg. 15)
Q2.7 When considering a ‘teamwork’ approach to maximize drug safety, name at least five different ‘individuals’ with a key role in this drug safety process for a given patient. (Pg. 17)
Q2.8 What are the most important common clinical scenarios which require more frequent (compared with normal monitoring frequencies) laboratory monitoring? (Pg. 18)
Q2.9 What are some important examples of ‘thresholds of concern’ and ‘critical values’ for laboratory tests commonly used in drug monitoring ( Table 2.1 )? (Pg. 18)
Q2.10 What are several important clinical strategies available for a specific abnormal lab value? (Pg. 18)
Q2.11 In the event a potentially serious complication of drug therapy does occur, what are some of the most important management options available to clinicians? (Pg. 19)

Introduction

This chapter is unique in the context of the entire book. The principles that follow are a blend of science, literature reports, personal experience, and common sense. Rather than provide references for the principles and examples used in this chapter, the reader is encouraged to selectively pursue more detailed information and literature references pertaining to examples cited here in the various chapters devoted to the respective drug or drug category. Most of the examples provided deal with systemic drug therapy in dermatology, given that the systemic drugs commonly prescribed pose a significantly greater potential risk to the patient than topical or intralesional therapeutic options.

Q2.1 Four words summarize the proactive approach to maximizing the safety of dermatologic drug therapy discussed in this chapter: anticipation , prevention , diagnosis , and management . The primary goals of maximizing drug safety are:

1.
Anticipation of which patients (comorbidities and other drugs the patient receives) and which drug regimens are at risk for various important adverse effects (AE);
2.
Prevention of AE of potential concern by taking appropriate proactive safety measures;
3.
Diagnosis at an early, reversible stage should an AE occur; and
4.
Management of the AE in a safe and effective, and often collaborative, manner.

I will present a number of general principles regarding how to maximize the safety and efficacy of systemic drug therapy. Each principle will be illustrated with several pertinent drug examples.

Unlike many medical specialties, dermatologists in general must take greater precautions with systemic drug therapy, for the following reasons. Systemic drugs used in this field have typically been developed for specialties such as rheumatology, oncology, infectious diseases, and transplantation surgery. These specialties in general care for patients with more serious, possibly life-threatening, illnesses than the majority of conditions for which dermatologists prescribe the various systemic drugs. Clinicians in any field are obliged to avoid creating a greater risk with drug therapy than the innate risk (in that specific patient) of the underlying disease to be treated. This statement is the underlying principle behind the need for careful monitoring of systemic drug therapy in dermatology. It is essential to maximize the safety and minimize the risk of this drug therapy.

How to optimally anticipate , prevent , diagnose , and manage specific drug AE to maximize drug safety is a central theme of this chapter and of the book as a whole. This is a broader viewpoint than merely ‘monitoring’ for AE. The goals of this broader approach are to (1) maximize overall drug safety for the patient, (2) improve the ‘emotional comfort’ of systemic drug therapy for the patient and physician, and (3) follow the appropriate ‘standards of care’ to minimize medicolegal risk. These overlapping goals are interdependent. For example, when appropriate standards of care are followed, the patient safety is the focus of these standards. In addition, when the patient’s safety and emotional comfort during drug therapy are truly of central importance to the physician, the medicolegal risk is negligible. This is particularly true if the patient assumes an active role in the decision making process for all aspects of any systemic drug therapy regimen, in turn forming a ‘therapeutic partnership’ with the prescribing physician.

It is somewhat challenging to define the definitive sources of these so-called ‘standards of care.’ Q2.2 In general, such standards come from one or more of the following sources:

1.
Specialty-based formal guidelines such as the American Academy of Dermatology ‘Guidelines of Care’;
2.
Individual pharmaceutical company guidelines for specific drugs, such as the therapeutic guidelines and informed consent packet for isotretinoin (iPLEDGE) in women of childbearing potential;
3.
The US Food and Drug Administration (FDA) Advisory Committee recommendations, such as those guidelines proposed in the early 1980s for monitoring the hematologic complications of dapsone;
4.
Consensus conference publications, such as the consensus guidelines published in 2004 for isotretinoin therapy in acne patients; and
5.
‘Dear Health Care Professional’ letters (formerly ‘Dear Doctor’ letters) from pharmaceutical companies, with careful oversight by the FDA, updating physicians and other health care providers nationally regarding recent findings for specific AE.

The reality is that the standards of care for a given drug are often a blend of several of these sources, with a certain amount of ambiguity as would be expected from such a mix.

Historically, these standards of care were based on local practices in the ‘community’ in which the physician practiced. Currently the realities of the ‘information age’ in which we practice tend to create a trend towards national, if not global, standards of care. Such standards should be considered guidelines, and not mandates, with room for flexibility as the patient’s individual circumstances, clinician’s experience, and scientific ‘evidence’ justify.

As far as possible, special efforts must always be made to ensure that the most serious adverse effects (SAE) ‘never’ occur. Q2.3 Characteristics of the most SAE given the highest priority in this chapter, and throughout the book, include at least several of the following:

1.
a sudden, precipitous onset;
2.
no early warning symptoms;
3.
no predictive laboratory tests;
4.
potentially irreversible; and
5.
a potentially serious outcome.

Examples of such high-priority AE include (1) hematologic complications (pancytopenia from azathioprine or methotrexate, agranulocytosis from dapsone), (2) isotretinoin teratogenesis, (3) corticosteroid (CS) osteonecrosis, (4) opportunistic infections from tumor necrosis factor (TNF) inhibitors and other biologic therapeutics, and progressive multifocal leukoencephalopathy from rituximab and efalizumab (off the market). Principles to minimize the likelihood of these and other complications follow in the four major sections of this chapter.

First, a few ‘baseline concepts.’ No matter how careful a physician may be, sooner or later ‘bad things’ will happen to a patient from drug therapy that he or she initiates. No medical risk reduction system is perfect, given the unpredictabilities of the human body. If the patient and physician can form a strong therapeutic partnership, and if the physician continues to work with the patient to promptly diagnose and manage any drug-induced complications, there can be a number of positive results: (1) the patient’s medical outcome is optimized, (2) the physician’s ethical obligations are met, and (3) the medicolegal risk is minimized. Nevertheless, the physician must take a ‘lifelong learner’ approach to any such unexpected complications, carefully analyzing the events leading to the specific drug complication, and learning how to minimize the likelihood of a similar therapeutic outcome in the future.

On the following pages of this chapter, 33 ‘principles,’ with over 90 specific drug therapy examples, are used to illustrate the clinical approach for maximizing the safety of dermatologic drug therapy.

Anticipation

This section is broken down into five subsections: (1) patient selection, (2) patient education, (3) baseline laboratory and related tests, (4) concomitant drug therapy—drug interactions, and (5) evolving guidelines—risk factors.

Patient Selection

Principle #1

Carefully compare the ‘risk’ of the disease to be treated with the ‘risk’ of the drug regimen planned (in that particular patient); thus a ‘risk–risk’ assessment:

The risk of high-dose systemic CS in severe pemphigus vulgaris versus the risk from the same CS regimen in patients with either pemphigus foliaceus or localized epidermolysis bullosa acquisita.
The risk of 6 to 12 months of cyclosporine for a patient with limited plaque-type psoriasis versus the risk of the same regimen in a patient with debilitating and extensive pyoderma gangrenosum.
The risk of 1 to 2 weeks of cyclosporine for a patient with Stevens-Johnson syndrome versus the risk of burn unit therapy.
The risk of an interleukin IL-17 or IL-23 inhibitor in a patient with severe psoriasis with components of metabolic syndrome versus therapy with methotrexate or cyclosporine.

Principle #2

Choose patients who can comprehend and comply with important instructions for preventing and monitoring the most serious potential complications of systemic drug therapy. Examples in which this principle is most important include the following:

The importance of avoiding abrupt cessation of long-term, high-dose prednisone therapy—risk of hypothalamo-pituitary axis (HPA) complications such as an addisonian crisis.
The pregnancy prevention measures which are of central importance in isotretinoin therapy for women of childbearing potential.
The importance of avoiding significant amounts of alcohol with long-term methotrexate therapy for severe psoriasis or in women of childbearing potential on long-term acitretin therapy for psoriasis.

Principle #3

All patients are not ‘created equal’ regarding the risk for various AE. Examples of patients at significantly increased risk for the following AE (beyond the specifics of the drug regimen) include:

Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes mellitus, renal insufficiency.
CS osteoporosis: postmenopausal women, especially those who are thin and inactive.
CS osteonecrosis: recent significant local trauma, alcohol abuse, cigarette smoking, and presence of underlying hypercoagulable conditions.
TNF inhibitor use in patients with a personal or family history of multiple sclerosis.

The bottom line is that individual patients must be carefully ‘matched’ with the safest and most effective drug regimen for the unique presentation of their dermatosis. This ‘match’ hinges on the various risk factors and demographic variables with which a specific patient presents. Perhaps the best example is the lesson provided by the specialty of rheumatology regarding the apparent lesser risk of methotrexate in rheumatoid arthritis (RA) patients compared with the historical risk of the same methotrexate therapy in psoriasis patients. This risk reduction was accomplished by (1) more careful patient selection of patients by rheumatologists, and (2) by the much lower risk of ‘metabolic syndrome’ in RA patients than in psoriasis patients.

Patient Education

The multiple variables regarding a given course of systemic drug therapy are often very difficult for physicians to master. Thus, it should come as no surprise that the specific drug regimens and risks of these various therapies discussed are much more difficult for patients (who typically lack medical training) to understand. Q2.4 The patient needs to understand at least the following information: (1) how to take the medication, specifically the correct dose and timing, (2) the expected AE, (3) what symptoms to report, and (4) the specific monitoring using laboratory and related diagnostic tests. Particularly when significant risks to important organs or body systems are discussed, the understandable emotional reaction of most patients makes long-term retention very difficult. The above points and other concepts form the basis of the following principles.

Principle #4

Careful and reasonably thorough patient education is essential to truly ‘informed consent’ (see Chapter 68 ):

Patients need to be active participants in therapeutic decision-making, which requires physicians to present the information in an understandable fashion.
In addition, the patient must be provided the opportunity to ask questions and be given adequate time to consider the therapeutic options presented.
The ‘perpetual’ question of what risks need to be discussed during informed consent always needs to be carefully considered; what would a ‘reasonable patient’ want to know as a rough guide.

Principle #5

Use patient handouts, written at a very understandable level, to reinforce important information and instructions concerning the drug therapy chosen:

The physician must emphasize the key information contained in the handout, but handouts are never a substitute for appropriate physician-patient communication.
The patient should be instructed to notify the physician if there are any questions pertinent to the handout provided.
The patient should be instructed to report any significant new symptoms that may develop subsequently (even if they are not sure these symptoms are attributed to the specific drug).
Sources for these handouts include National Psoriasis Foundation (major systemic therapies for psoriasis, including biologics), various pharmaceutical companies (acitretin/Soriatane), the American Medical Association (CS and many others), and various online sources. Consider creating your own personalized patient education handouts regarding specific drugs you commonly prescribe.

Principle #6

Educate your patients regarding groups or clusters of symptoms, which together are important for the detection of potentially serious drug-induced complications. The grouping of these symptoms may not be emphasized in the above-mentioned handouts:

CS osteonecrosis: focal, significant joint pain (especially hip, knee, shoulder) with decreased range of motion of the affected joint.
Isotretinoin pseudotumor cerebri: headache, visual change, nausea, and vomiting.
All current biologic therapeutics and opportunistic infections: fever plus localizing symptoms such as a cough.
Dapsone (or minocycline) hypersensitivity syndrome (DRESS): fever, fatigue, sore throat, adenopathy, and morbilliform eruption.

A ‘two-way street’ of open communication between patient and physician is essential in maximizing the safety of systemic drug therapy. Any extra time the physician spends in this communication process should pay great dividends with regard to improved therapeutic outcomes.

Baseline Laboratory and Related Tests

Any organ system with potential for drug-induced complications requires a baseline evaluation before initiating therapy. There are very few exceptions to this principle. It stands to reason that existing pathology in an organ system, for which a given drug has the potential to induce abnormalities, will increase the likelihood of further injury to this organ system.

Principle #7

Assess the baseline status of any potential target organ or site of excretion for a given drug. Similarly, if a drug can induce a metabolic abnormality, check for baseline presence of this metabolic defect if such testing is currently available:

Baseline liver function tests and hepatitis viral serology: methotrexate hepatotoxicity (methotrexate ‘target’ organ) and with the full spectrum of biologics.
Baseline renal function assessment; at least testing serum creatinine, and possibly creatinine clearance: methotrexate hepatotoxicity or pancytopenia (site of methotrexate excretion).
Baseline (at least in the first month) comprehensive eye examination, including visual fields, in patients to receive hydroxychloroquine therapy.
Baseline testing for hyperglycemia or hyperlipidemia: prednisone therapy (metabolic abnormalities aggravated by prednisone).
Baseline testing for latent tuberculosis for all biologic therapeutics regardless of the indication. The choice of tuberculosis testing method (tuberculin test or interferon-γ release assay such as T-spot TB or Quantiferon Gold) is not yet fully clarified.

Principle #8

Use the most optimal tests that predict which patients are at increased risk for a specific AE. Typically such tests are ordered only at baseline. (Ideally many more of these predictive tests will be available in the future.):

Baseline glucose-6-phosphate dehydrogenase (G6PD) level: predicts magnitude of risk for dapsone hemolysis. (This test does not predict which patients are at risk for dapsone agranulocytosis or dapsone hypersensitivity syndrome.)
Baseline thiopurine methyltransferase level: predicts risk for azathioprine hematologic complications as well as guiding optimal azathioprine dosing. (This test does not predict azathioprine hepatotoxicity or hypersensitivity syndrome reactions.)

There are a few select tests for which a baseline determination is not required. Near the end of long-term high-dose prednisone therapy, a morning cortisol determination (usually ∼8:30 AM ) may be of value in assessing HPA function; a baseline determination is virtually never indicated. Some tests may require a delayed baseline determination. I formerly requested a ‘delayed baseline’ ultrasound-guided liver biopsy for methotrexate patients after 6 to 12 months of therapy, once it is clear that the patient tolerates the drug, benefits from the drug, and requires long-term methotrexate therapy. In current practice, a fibroscan after 6 to 12 months of therapy is appropriate. Still, overall the general rule holds: if you plan on monitoring a specific test during therapy with a given systemic drug, it is prudent to determine the baseline status of that specific test.

Concomitant Drug Therapy—Drug Interactions

Chapter 66 is devoted entirely to the subject of drug interactions of importance to the dermatologist and other physicians using similar medications. However, a few principles must still be addressed in this setting. The vast majority of drug interactions can be anticipated, and thus prevented. Truly life-threatening drug interactions are quite uncommon and virtually always have been well publicized. Q2.5 The following are principles dealing with three categories of drug interactions of central importance to maximizing the safety of systemic drug therapy.

Principle #9

Anticipate (and avoid) drug combinations that have overlapping target organs of potential toxicity:

Tetracycline or minocycline plus isotretinoin: pseudotumor cerebri.
Hydroxychloroquine plus chloroquine: antimalarial retinopathy. (It is acceptable practice to combine quinacrine with either of these two drugs, as quinacrine alone does not induce a retinopathy.)
Methotrexate and a second-generation retinoid (previously etretinate, now acitretin): probably an increased risk for hepatotoxicity.

Principle #10

Anticipate interactions involving two drugs that alter the same metabolic pathway:

Methotrexate and trimethoprim/sulfamethoxazole: increased risk for pancytopenia, given that these drugs inhibit folate metabolism.
Azathioprine and allopurinol or febuxostat: increased risk for hematologic complications, as these drugs affect parallel purine metabolic pathways.

Principle #11

Anticipate (and avoid) drug combinations metabolized by the same cytochrome P-450 (CYP) pathway, particularly if there is a narrow therapeutic index for one of the drugs involved:

Rifampin (CYP3A4 enzyme inducer) plus hormonal contraceptives: loss of efficacy of the contraceptive with the potential for an unintended pregnancy.
Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors) plus cyclosporine: increased risk for renal toxicity because of increased cyclosporine blood levels.

This area of medicine is very complicated and it is very difficult to stay ‘current’ (see Chapter 66 ). At times, recently released drugs have important, potentially life-threatening interactions which are discovered only years later. The potential for torsades de pointes with life-threatening cardiac arrhythmias from terfenadine, astemizole, or cisapride (elucidated several years after the drugs’ release) in the presence of certain CYP enzyme inhibitors illustrates this point. Do your best to stay current: liberally use the numerous electronic resources for information on drug interactions. As a backup, use of your hospital’s drug information pharmacists is highly recommended to more effectively deal with this challenging area of medicine.

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